Discovery and optimization of 3,4,5-trimethoxyphenyl substituted triazolylthioacetamides as potent tubulin polymerization inhibitors

Fang Yang, Cai Ping He, Peng Cheng Diao, Kwon Ho Hong, Jin Jun Rao, Pei Liang Zhao

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 μM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 μM, which was almost as active as that of CA-4 (IC50 = 4.2 μM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin.

Original languageEnglish (US)
Pages (from-to)22-27
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2019

Bibliographical note

Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (No. 21372113 ), and the Science and Technology Program of Guangzhou , China (No. 201707010198 ).

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • Antiproliferative activity
  • Synthesis
  • Triazolylthioacetamides
  • Tubulin polymerization

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